Introduction: In the post-Helicobacter pylori era, autoimmune gastritis (AIG) is attracting increasing attention as an origin of gastric cancer. Here, we performed clinicopathological examination of gastric cancer complicating AIG treated in our hospital. Methods: Eighty-six early gastric cancer lesions complicating AIG in 50 patients were treated by endoscopic submucosal dissection (ESD) at our hospital in 2008–2022. Their clinicopathological characteristics were compared with those of a control group comprising 2,978 early gastric cancer lesions (excluding lesions in the remnant stomach after surgery) in 2,278 patients treated by ESD during the same period. Results: Mean age was significantly higher in the AIG group than in the control group (74.7 years vs. 70.9 years; p < 0.01). In the respective groups, the occurrence rate of synchronous/metachronous lesions was 38.0% and 20.4% (p < 0.01), the ratio of longitudinal cancer locations (upper/middle/lower third [U/M/L]) was 27/32/27 and 518/993/1,467 (p < 0.01), the ratio of circumferential cancer locations (lesser curvature/greater curvature/anterior wall/posterior wall) was 25/31/12/18 and 1,259/587/475/657 (p < 0.01), the ratio of major macroscopic types (I/IIa/IIb/IIc) was 13/38/5/30 and 65/881/220/1,812 (p < 0.01). The rates of multiple gastric cancer and cancers in the U region, at the greater curvature, and of protruding types were significantly higher in the AIG group. Conclusion: The occurrence rate of multiple gastric cancer was significantly higher in gastric cancer complicating AIG (approximately 40%), and compared with the control group, the proportions of cancers at the U region, at the greater curvature, and of protruding types were significantly higher.

The number of newly infected patients with Helicobacter pylori is decreasing due to eradication therapy for gastritis caused by H. pylori infection [1, 2], and autoimmune gastritis (AIG) is gaining increasing attention. In AIG, inflammation and atrophic changes occur mainly in the oxyntic gland area due to an autoimmune mechanism involving anti-parietal cell antibodies (PCAs) [3, 4]. AIG was reported to have a prevalence of 0.5% in a study of Japanese medical checkups [5]. AIG has various complications including NET (neuroendocrine tumor), among which gastric cancer is the most critical and directly affects prognosis. Severely atrophic mucosa, like atrophic gastritis caused by H. pylori, can be an origin of gastric cancer; it causes DNA methylation, which is thought to increase the risk of carcinogenesis [6]. However, details of gastric cancer occurring in AIG are largely unknown, and Rugge et al. [7] reported that AIG does not increase the risk of gastric cancer, rather likely due to a result from an unrecognized previous/current H. pylori infection. Here, we investigated the clinicopathological characteristics of gastric cancer complicating AIG.

Indications and Patients

A total of 3,970 lesions were treated by ESD at our hospital from January 2008 to December 2022. Lesions that were not gastric cancer, such as adenomas and NET, and those in the remnant stomach after surgery were excluded, leaving 3,064 lesions in 2,328 patients. Among them, 86 lesions in 50 patients were early gastric cancer complicating AIG (Fig. 1a, b), and their clinicopathological characteristics were compared with those of the control group (2,978 lesions in the remaining 2,278 patients) (Fig. 2). In the present study, we defined AIG cases based on characteristic endoscopic findings, such as significant corpus-dominant atrophy (Fig. 3a) and sticky adherent dense mucus (Fig. 3b), and positive autoantibodies, either anti-PCAs or anti-internal factor antibodies (IFAs). This study was approved by the Ethics Committee of Toranomon Hospital (No.  2161).

Fig. 1.

Endoscopic image of early gastric cancer arising from AIG. a Case 1: 80-year-old male. A 12-mm large raised lesion was found in the greater curvature of the upper gastric body. The background gastric mucosa showed severe atrophy. b Case 2: 72-year-old male. Two flattened lesions, 25 mm and 12 mm in size, were seen side by side in the greater curvature of the middle body. After spraying indigocarmine, lesion boundaries became more defined.

Fig. 1.

Endoscopic image of early gastric cancer arising from AIG. a Case 1: 80-year-old male. A 12-mm large raised lesion was found in the greater curvature of the upper gastric body. The background gastric mucosa showed severe atrophy. b Case 2: 72-year-old male. Two flattened lesions, 25 mm and 12 mm in size, were seen side by side in the greater curvature of the middle body. After spraying indigocarmine, lesion boundaries became more defined.

Close modal
Fig. 2.

Study flow diagram.

Fig. 2.

Study flow diagram.

Close modal
Fig. 3.

Endoscopic appearance of AIG. a The disappearance of folds without an atrophic border is observed on the entire area of the greater curvature in the corpus. b Sticky adherent dense mucus with creamy white color is observed in the corpus to the fundus.

Fig. 3.

Endoscopic appearance of AIG. a The disappearance of folds without an atrophic border is observed on the entire area of the greater curvature in the corpus. b Sticky adherent dense mucus with creamy white color is observed in the corpus to the fundus.

Close modal

Evaluations

We retrospectively analyzed patient background factors, endoscopic findings, histopathology, H. pylori status, endoscopic findings of the treated lesion, and histopathology. All endoscopic findings were reviewed for data related to the size, location, and gross findings of the tumor. Longitudinal tumor locations were classified into the upper third (cardia, fundus, and upper body), middle third (mid-body and lower body), and lower third (angle, antrum, and prepylorus) of the stomach (U/M/L) [8]. Circumferential tumor locations were defined as the anterior wall, posterior wall, lesser curvature, and greater curvature. The largest diameter of the gastric lesion was measured as the tumor size. The endoscopic gross morphology of the tumors was classified based on the Paris Classification [9].

Histological Assessment

The resected specimen was cut into 2-mm slices after fixation in 10% formalin. Histological type, depth of invasion, lateral and vertical margins, and lymphovascular invasion were evaluated in each slice according to the Japanese Classification of Gastric Carcinoma [8].

R0 resection was defined as resection in one piece with tumor-free margins. However, this definition did not include depth of invasion, lymphovascular infiltration, or type of adenocarcinoma. Curative resection was defined as R0 resection without invasion into a lymph duct or venous duct and meeting one of the following four Japanese Gastric Cancer Association specifications [10]: (i) differentiated-type mucosal cancer without ulcer (UL); (ii) differentiated-type mucosal cancer with UL and tumor diameter (TD) ≤ 30 mm; (iii) differentiated-type minute submucosal cancer (SM1) and TD ≤30 mm; (iv) undifferentiated-type mucosal cancer without UL and TD ≤20 mm.

Tumor histopathology was evaluated with ESD specimens, and mixed carcinoma was defined as the presence of both differentiated and undifferentiated histologic types. TD was also evaluated in ESD specimens.

Complications

Postoperative bleeding was defined as bleeding requiring emergency endoscopy or transfusion, or as a decrease in hemoglobin level of >2 g/dL following ESD. Perforation was diagnosed endoscopically or based on the presence of free air on plain abdominal X-ray or computed tomography after ESD.

Antibody Tests

Anti-PCA was determined using an indirect fluorescent antibody test by using a commercially available kit (Fujirevio Inc., Tokyo, Japan). APCA positivity was defined as an APCA serum level >10 times. Anti-IFA was determined using a commercially available kit (Beckman Coulter, Brea, CA, USA) based on a chemiluminescent enzyme immunoassay.

Determination of H. pylori Infection

H. pylori-uninfected status was defined as no history of H. pylori eradication therapy and had negative results for both serum anti-H. pylori IgG antibodies and stool H. pylori antigens. H. pylori-infected status was defined as a history of H. pylori eradication therapy, or positive results for either serum anti-H. pylori IgG antibodies or stool H. pylori antigens.

Statistical Analysis

Data are presented as the mean ± standard deviation. Statistical analysis was performed using the χ2 test and Mann-Whitney U test. All statistical analyses were performed using Stata version 14 (StataCorp, College Station, TX, USA). A p value of <0.05 was considered significant.

Patient Background

Patient background characteristics are shown in Table 1. The male to female ratio was not significantly different between the AIG group and the control group (36:14 vs. 1,745:533, p = 0.45). The occurrence rate of synchronous and metachronous gastric cancer was significantly higher in the AIG group than in the control group (19 [38.0%] vs. 464 [20.4%], p < 0.01). In the AIG group, PCA was 10× in 24 patients (48%) and ≥20× in 24 patients (48%). Eleven patients (22%) were positive for IFA. Thirty-two patients (64.0%) were H. pylori infected, while 18 (36.0%) were H. pylori uninfected. Pernicious anemia and autoimmune diseases were present as complications in 2 patients (4.0%) and 5 (10%), respectively. The following non-cancerous gastric lesions were found: NET in 3 patients (6.0%), adenomas in 5 (10.0%), and hyperplastic polyps in 17 (37.0%).

Table 1.

Patient background characteristics

AIG (50)Control (2,278)p value
Age, mean±SD, years 77.0±7.5 70.4±9.9 <0.01 
Sex, n (%)   0.45 
 Male 36 (72.0) 1,745 (76.6)  
 Female 14 (28.0) 533 (23.4)  
Multiple gastric cancer, n (%) 19 (38.0) 464 (20.4) <0.01 
PCA, n (%) 
 10 24 (48.0)   
 20 4 (8.0)   
 40 6 (12.0)   
 80 7 (14.0)   
 160 4 (8.0)   
 320 2 (4.0)   
 640 1 (2.0)   
IFA, n (%) 
 Positive 11 (22.0)   
Helicobacter pylori status, n (%) 
 Infected 32 (64.0)   
 Uninfected 18 (36.0)   
Comorbidity, n (%) 
 Pernicious anemia 2 (4.0)   
 Autoimmune disease 5 (10.0)   
Concomitant gastric disease, n (%) 
 Adenoma 5 (10.0)   
 NET 3 (6.0)   
 Hyperplastic polyp 17 (34.0)   
AIG (50)Control (2,278)p value
Age, mean±SD, years 77.0±7.5 70.4±9.9 <0.01 
Sex, n (%)   0.45 
 Male 36 (72.0) 1,745 (76.6)  
 Female 14 (28.0) 533 (23.4)  
Multiple gastric cancer, n (%) 19 (38.0) 464 (20.4) <0.01 
PCA, n (%) 
 10 24 (48.0)   
 20 4 (8.0)   
 40 6 (12.0)   
 80 7 (14.0)   
 160 4 (8.0)   
 320 2 (4.0)   
 640 1 (2.0)   
IFA, n (%) 
 Positive 11 (22.0)   
Helicobacter pylori status, n (%) 
 Infected 32 (64.0)   
 Uninfected 18 (36.0)   
Comorbidity, n (%) 
 Pernicious anemia 2 (4.0)   
 Autoimmune disease 5 (10.0)   
Concomitant gastric disease, n (%) 
 Adenoma 5 (10.0)   
 NET 3 (6.0)   
 Hyperplastic polyp 17 (34.0)   

PCA, parietal cell antibody; IFA, internal factor antibody; NET, neuroendocrine tumor; SD, standard deviation.

Clinicopathological Features of Gastric Cancer in the AIG and Control Groups

Clinicopathological characteristics are shown in Table 2. Mean age was significantly higher in the AIG group than in the control group (74.7 ± 8.2 years vs. 70.9 ± 9.8 years, p < 0.01). There was no significant difference in the male to female ratio or tumor size between the groups. The ratio of longitudinal tumor locations (U/M/L) was 27/32/27 in the AIG group and 518/993/1,467 in the control group (p < 0.01), and the ratio of circumferential locations (lesser curvature/greater curvature/anterior wall/posterior wall) was 25/31/12/18 in the AIG group and 1,259/587/475/657 in the control group (p < 0.01): the proportions of lesions at the U region and at the greater curvature were significantly higher in the AIG group. The ratio of major macroscopic types (I/IIa/IIb/IIc) was 13/38/5/30 in the AIG group and 65/881/220/1,812 in the control group (p < 0.01): the proportion of protruding types (0-I and 0-IIa) was significantly higher in the AIG group. Pathological type, depth of invasion, lymphovascular invasion, perforation rate, and postoperative bleeding rate were not significantly different between the groups. The complete resection rates were not significantly different (98.8% vs. 95.9%), but the curative resection rate was significantly higher in the AIG group than in the control group (95.3% vs. 87.5%, p < 0.05).

Table 2.

Clinicopathological features of gastric cancer in the AIG and control groups

AIG (86)Control (2,978)p value
Age, mean±SD, years 74.7±8.2 70.9±9.8 <0.01 
Sex, n (%)   0.71 
 Male 69 (80.2) 2,339 (78.5)  
 Female 17 (19.8) 639 (21.5)  
Tumor size (mean±SD) 16.6±12.7 17.8±14.8 0.79 
Location, n (%)   <0.01 
 Upper third 27 (31.4) 518 (17.4)  
 Middle third 32 (37.2) 993 (33.3)  
 Lower third 27 (31.4) 1,467 (49.3)  
Tumor circumference, n (%)   <0.01 
 Lesser curvature 25 (29.1) 1,259 (42.3)  
 Greater curvature 31 (36.1) 587 (19.7)  
 Anterior wall 12 (14.0) 475 (16.0)  
 Posterior wall 18 (20.9) 657 (22.1)  
Morphological type, n (%)   <0.01 
 0-I 13 (15.1) 65 (2.2)  
 0-IIa 38 (44.2) 881 (30.0)  
 0-IIb 5 (5.8) 220 (7.4)  
 0-IIc 30 (34.9) 1,812 (60.9)  
Histopathology, n (%)   0.48 
 Differentiated carcinoma 77 (89.5) 2,520 (84.6)  
  Differentiated mixed type adenocarcinoma 7 (8.1) 281 (9.4)  
  Undifferentiated mixed type adenocarcinoma 1 (1.2) 49 (1.7)  
 Undifferentiated carcinoma 1 (1.2) 128 (4.3)  
Depth of invasion, n (%)   0.31 
 M 79 (91.9) 2,616 (87.8)  
 SM1 6 (7.0) 229 (7.7)  
 Deeper than SM2 1 (1.2) 133 (4.5)  
Lymphatic invasion, n (%) 108 (3.6) 0.07 
Vascular invasion, n (%) 1 (1.2) 61 (2.1) 0.57 
HM1, n (%) 66 (2.2) 0.16 
VM1, n (%) 1 (1.2) 61 (2.1) 0.57 
R0 resection, n (%) 85 (98.8) 2,855 (95.9) 0.17 
Curative resection, n (%) 82 (95.3) 2,605 (87.5) <0.05 
Complication, n (%) 
 Perforation 3 (3.5) 41 (1.4) 0.11 
 Postoperative bleeding 3 (3.5) 177 (5.9) 0.34 
AIG (86)Control (2,978)p value
Age, mean±SD, years 74.7±8.2 70.9±9.8 <0.01 
Sex, n (%)   0.71 
 Male 69 (80.2) 2,339 (78.5)  
 Female 17 (19.8) 639 (21.5)  
Tumor size (mean±SD) 16.6±12.7 17.8±14.8 0.79 
Location, n (%)   <0.01 
 Upper third 27 (31.4) 518 (17.4)  
 Middle third 32 (37.2) 993 (33.3)  
 Lower third 27 (31.4) 1,467 (49.3)  
Tumor circumference, n (%)   <0.01 
 Lesser curvature 25 (29.1) 1,259 (42.3)  
 Greater curvature 31 (36.1) 587 (19.7)  
 Anterior wall 12 (14.0) 475 (16.0)  
 Posterior wall 18 (20.9) 657 (22.1)  
Morphological type, n (%)   <0.01 
 0-I 13 (15.1) 65 (2.2)  
 0-IIa 38 (44.2) 881 (30.0)  
 0-IIb 5 (5.8) 220 (7.4)  
 0-IIc 30 (34.9) 1,812 (60.9)  
Histopathology, n (%)   0.48 
 Differentiated carcinoma 77 (89.5) 2,520 (84.6)  
  Differentiated mixed type adenocarcinoma 7 (8.1) 281 (9.4)  
  Undifferentiated mixed type adenocarcinoma 1 (1.2) 49 (1.7)  
 Undifferentiated carcinoma 1 (1.2) 128 (4.3)  
Depth of invasion, n (%)   0.31 
 M 79 (91.9) 2,616 (87.8)  
 SM1 6 (7.0) 229 (7.7)  
 Deeper than SM2 1 (1.2) 133 (4.5)  
Lymphatic invasion, n (%) 108 (3.6) 0.07 
Vascular invasion, n (%) 1 (1.2) 61 (2.1) 0.57 
HM1, n (%) 66 (2.2) 0.16 
VM1, n (%) 1 (1.2) 61 (2.1) 0.57 
R0 resection, n (%) 85 (98.8) 2,855 (95.9) 0.17 
Curative resection, n (%) 82 (95.3) 2,605 (87.5) <0.05 
Complication, n (%) 
 Perforation 3 (3.5) 41 (1.4) 0.11 
 Postoperative bleeding 3 (3.5) 177 (5.9) 0.34 

SD, standard deviation; HM, horizontal margin; VM, vertical margin; M, mucosa; SM, submucosa; SM2, submucosal layer >500 µm from mucosal layer.

AIG is a chronic progressive gastritis in which parietal cells are damaged and lost due to cytotoxic T-cell-mediated autoimmunity, and autoantibodies (PCA) against the proton pump (H+/K+ ATPase) are produced. Upon progression to advanced atrophic gastritis, hypochlorhydria and achlorhydria occur due to decreases in and loss of parietal cells. At the end stage, malabsorption of vitamin B12 occurs due to deficiency in intrinsic factor secreted from parietal cells, resulting in the onset of pernicious anemia.

Endoscopic findings of AIG vary greatly depending on disease progression and influence of H. pylori infection. Corpus-dominant advanced atrophy is a typical finding of AIG and is often the first clue for its diagnosis (Fig. 1). In a Japanese multicenter study [11], O4 (O–P) according to the modified Kimura-Takemoto classification [12] was the most common finding (90.1%), followed by O1–O3 (5.9%). To accurately diagnose corpus-dominant advanced atrophy, the key point in the endoscopic technique is to fully extend the gastric fold; insufficient air may cause this finding to be missed. Other characteristic findings include sticky adherent dense mucus and remnant oxyntic mucosa, which were found in 32.4% and 31.5% of patients with AIG, respectively [11]. Sticky adherent dense mucus is white-yellowish mucus that adheres in the area from the fundus to the upper body of the stomach and cannot be easily removed by rinsing with water. Remnant oxyntic mucosa is the mucosa in a confined area that remains unaffected while non-uniform mucosal atrophy occurred in the oxyntic gland region; it is called the pseudopolyp-like type when protrusion is prominent. In addition, hyperplastic polyps and white globe appearance were reported as characteristic findings [8].

AIG is considered an origin of gastric cancer [13, 14]. The incidence rate of gastric cancer in AIG is reported to be 1–3% [15‒18], and a 19-year prospective study by Miceli et al. reported that gastric cancer was found in 7 of 270 patients (2.6%) [19]. Meta-analysis of 12 clinical studies by Vannella et al. [20] showed that the gastric cancer relative risk was 6.8 (95% confidence interval: 2.6–18.1) and the gastric cancer incidence rate was 0.27% per person-years in patients with pernicious anemia. Reported risk factors for gastric cancer include pernicious anemia, advanced atrophic changes, the presence of intestinal metaplasia, long-time persisting type A gastritis, and aged ≥50 years [13, 21‒23], all of which are characteristics of the late-stage AIG; therefore, gastric cancer can be regarded as one of complications of AIG. In this study, all patients were aged ≥50 years and had advanced atrophy with intestinal metaplasia, but only a small proportion (4%) had pernicious anemia.

This study showed that significantly more lesions of early gastric cancer complicating AIG were protruding types (macroscopic type 0-I or 0-IIa). Compared with the control group, depressed lesions were less common, probably due to highly reduced gastric acid secretion in AIG. Lesions occurred equally across the longitudinal locations (U, M, and L), suggesting no predilection site. However, significantly more lesions were found at the U region compared with the control group, and thus, this area needs to be observed with extra care in AIG. For the circumferential location, significantly more lesions occurred at the greater curvature in AIG. The greater curvature was a less likely site to find lesions in the control group, but careful observation is required when patients have AIG.

The most prominent characteristic of the AIG group found in this study was a high occurrence rates of multiple gastric cancer cases. Synchronous or metachronous gastric cancer was found in approximately 40% of patients in the AIG group, and the proportion was significantly higher than in the control group. This needs to be kept in mind at follow-up examination.

Histology showed that many gastric cancers in AIG were a highly differentiated type (papillary adenocarcinoma in particular) [24]. Also, the prognosis of gastric cancer was reportedly more favorable when complicating AIG than when AIG was absent [25]. In this study, a majority of cases in the AIG group (89.5%) were differentiated type lesions, albeit without a significant difference compared with the control group. This may be a reason for the significantly higher curative resection rate in the AIG group in this study: another possible reason is that close follow-up was performed for the AIG group because more patients had multiple gastric cancer and advanced atrophic lesions in the AIG group than in the control group. It is important not to miss endoscopic findings characteristic of AIG and to conduct regular surveillance bearing in mind the characteristics of early gastric cancer as a complication of AIG.

There are some limitations in this study. First, this was a retrospective single-center study with a limited number of patients. Second, AIG was diagnosed based on the following criteria: (1) endoscopic findings indicating advance open-type atrophy in the gastric corpus and (2) positive results for either PCA or IFA, and thus, there could be some false-positive cases of AIG. The definition of PCA as positive from 10x may also have contributed to the increase in the false positive rate. Pathological examination should have been performed in all cases to confirm the diagnosis of AIG. Third, not all patients were tested for PCA and/or ICA, and since the endoscopist focused on patients suspected of having AIG, it was possible that some patients in the control group actually had AIG. A prospective study wherein PCA and ICA are measured in all patients who undergo ESD is awaited.

The occurrence rate of multiple gastric cancer was significantly higher in early gastric cancer complicating AIG. The proportions of lesions at the U region, at the greater curvature, and of protruding types were significantly higher in the AIG group than in the control group. For patients with AIG, it is ideal to conduct close follow-up because many have multiple gastric cancer, and the U region and greater curvature require particularly careful observation.

Because of the retrospective nature of this study, written informed consent was not obtained from the patients and the need for informed consent was waived by the Ethics Committee of Toranomon Hospital. The study was conducted according to the ethical principles stated in the 1964 Helsinki Declaration. In our study, research and publication ethics were followed, and the relevant rules were followed as well. Ethical approval of the study was obtained from the Ethics Committee of Toranomon Hospital (Approval No. 2161).

The authors have no conflict of interest to declare.

The authors declare that this study has received no financial support.

Nomura designed the study and wrote the initial draft of the manuscript. Hoteya and Kikuchi contributed to data interpretation and critical revision of the manuscript for important intellectual content. All other authors (Kawai, Ochiai, Okamura, Suzuki, Hayasaka, Mitsunaga, Odagiri, Yamashita, and Matsui) contributed to data collection and interpretation and critical review of the manuscript. All authors have read and approved the final version of the manuscript and have agreed to the accountability of all aspects of the study, ensuring that any queries related to the accuracy or integrity of any part of the work are answerable.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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